The Role of MDM2 in Promoting Genome Stability versus Instability
Abstract
:1. Introduction
2. Mouse Double Minute 2 (MDM2) Isoforms
3. Role of DNA Damage in Stability and Modification of MDM2
4. The Balancing Act of MDM2 and p53 Expression—Implications for Cell Survival
5. p53-Independent Role of MDM2 in Genome Instability and Survival
6. Therapeutic Considerations and Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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MDM2 Isoform | MDM2-A | MDM2-B | MDM2-C |
---|---|---|---|
Model In Vitro and/or In Vivo | MDM2-A transgenic mice; MDM2-A expressing transgenic mouse embryonic fibroblasts (MEFs); and, MDM2-A retrovirally transduced wildtype MEFs | Human lung cancer and colorectal cancer cell lines | Human breast cancer cell lines; human liposarcoma, breast carcinoma tissues, and osteosarcoma cells |
MDM2 Isoform Expression | Increased expression of MDM2-A (75 kDa) in human cancer cells and/or tissues such as breast cancer and Hodgkin’s Lymphoma | Most common MDM2 isoform. Increased expression of MDM2-B (48 kDa) observed in in human cancers and/or tissues such as colorectal cancer, breast cancer, and Hodgkin’s Lymphoma | Increased expression of MDM2-C (85 kDa) in human cancer cells and/or tissues of breast cancer, osteosarcoma, and chronic myelogenous leukemia |
p53 Expression | Accumulation of wildtype p53 activity | Accumulation of wildtype and mutant p53 | p53 independent transformation function; does not function by inhibiting p53 transcriptional activity and does not show role in p53 degradation pathway |
Mechanism | MDM2-A lacks wildtype p53 binding region but binds and sequesters FL-MDM2 to prevent FL-MDM2-dependent-degradation of wildtype p53 | MDM2-B lacks the wildtype p53 binding domains but can interact with FL- MDM2 to prevent degradation of mutant p53 | p53-independent function for cell proliferation; MDM2-C lacks p53 binding domain but exact mechanism requires further investigation |
Effectors of MDM2 | Effect on MDM2 Function |
---|---|
PTEN | Transcriptional inhibition |
NF-κB | Transcriptional activation |
Raf | Transcriptional activation |
Smad3/4 | Transcriptional activation |
E2F1 | Transcriptional inhibition |
ATM | MDM2 phosphorylation at S394 and/or S395 is required for p53 accumulation, stabilization and activation |
c-AbI | Tyrosine phosphorylation of MDM2 facilitates MDM2-MDMX complex formation and regulates p53 stabilization |
AKT | Phosphorylation of MDM2 at residues S166 and S188 inhibits its self-ubiquitination and at S186 Akt enhances the ubiquitination-promoting function of MDM2 which results in reduction of p53 protein |
Daxx | Stabilizes; enhances interaction between Mdm2 & Hausp |
Cyclin G | Dephosphorylation of Mdm2 |
MdmX | Inhibits auto-ubiquitination of MDM2 E3 ligase activity |
Elf4/Mef | Transcriptional activation |
p19ras | Blocks Mdm2-p73 interaction |
Seladin-1 | Blocks Mdm2-p53 interaction |
RPS3/S7/S27 | Blocks Mdm2-p53 interaction |
L5/L11/L23/L26 | Blocks Mdm2 ubiquitination of p53 |
p38 | p300 binds to p53 and MDM2; there is evidence that p38 can phosphorylate p300 and increase capacity of MDM2 to promote p300 degradation. |
Cyclin a-CDK complexes | phosphorylate MDM2 and affect interaction of MDM2 with proteins |
p14ARF | E3 ligase inhibition in the context of MDM2-p53 interactionsE3 ligase activation in the context of MDM2-MDMX interactions |
MTBP | Binds to MDM2 and Induces a G1 Arrest |
Targets of MDM2 | Result of Interaction with MDM2 |
---|---|
p53 | Decreases p53 activity |
p73 | Decreases p53 activity |
p63 | Decreases p53 activity |
HDAC | Mdm2-HDAC interaction facilitates p53 acetylation |
Nbs1 | Inhibition of double strand break repair |
β2 Androgen receptor | Ubiquitination and degradation via Akt/Mdm2 |
RB | Inhibits RB binding to E2F1 |
ATF3 | Ubiquitination and degradation |
E-cadherin | Ubiquitination and degradation |
NF-κB/p65 | MDM2 induces NF-κB/p65 expression transcriptionally through Sp1-binding sites |
Chk2 | Ubiquitination and degradation |
NUMB | Alters subcellular localization; Ubiquitination and degradation |
Compound Developer | Clinical Trial Phase and Status | References |
---|---|---|
RO5045337/RG7112 | phase I | [100] |
MDM2 antagonist | Completed | |
(Roche) | ||
RO5503781/RG7388/Idasanutlin | phase I | [101] |
MDM2 antagonist | Completed | |
(Roche) | ||
AMG232 | phase I | [102] |
MDM2 antagonist | Completed | |
(Amgen) | ||
CGM097 | phase I | [103] |
MDM2 antagonist | Ongoing but not recruiting | |
(Novartis) | ||
DS-3032b/Benzodiazepinedione | phase I | [104] |
MDM2 antagonist | Recruiting participants | |
(Daiichi Sankyo) | ||
SAR405838 | phase I | [105] |
MDM2 antagonist | Completed | |
(Sanofi S.A.) | ||
MK-8242/SCH 900242 | phase I | [106] |
MDM2 antagonist | Terminated | |
(Merck) | ||
ALRN-6924 | Phase I/2a | [94] |
MDM2/MDMX dual antagonist | Ongoing recruiting | |
(Aileron Therapeutics) |
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Saadatzadeh, M.R.; Elmi, A.N.; Pandya, P.H.; Bijangi-Vishehsaraei, K.; Ding, J.; Stamatkin, C.W.; Cohen-Gadol, A.A.; Pollok, K.E. The Role of MDM2 in Promoting Genome Stability versus Instability. Int. J. Mol. Sci. 2017, 18, 2216. https://doi.org/10.3390/ijms18102216
Saadatzadeh MR, Elmi AN, Pandya PH, Bijangi-Vishehsaraei K, Ding J, Stamatkin CW, Cohen-Gadol AA, Pollok KE. The Role of MDM2 in Promoting Genome Stability versus Instability. International Journal of Molecular Sciences. 2017; 18(10):2216. https://doi.org/10.3390/ijms18102216
Chicago/Turabian StyleSaadatzadeh, M. Reza, Adily N. Elmi, Pankita H. Pandya, Khadijeh Bijangi-Vishehsaraei, Jixin Ding, Christopher W. Stamatkin, Aaron A. Cohen-Gadol, and Karen E. Pollok. 2017. "The Role of MDM2 in Promoting Genome Stability versus Instability" International Journal of Molecular Sciences 18, no. 10: 2216. https://doi.org/10.3390/ijms18102216